J. Med. Chem. 2008, 51, 4351–4355
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Discovery of 4-Amino and 4-Hydroxy-1-aroylindoles as Potent Tubulin Polymerization Inhibitors Jing-Ping Liou,† Zi-Yi Wu,† Ching-Chuan Kuo,‡ Chi-Yen Chang,‡ Pei-Yi Lu,† Chi-Ming Chen,† Hsing-Pang Hsieh,*,¶ and Jang-Yang Chang*,‡,§ College of Pharmacy, Taipei Medical UniVersity, Taipei 110, Taiwan, Republic of China, National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China, DiVision of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan, Republic of China, and DiVision of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung UniVersity Hospital, Tainan 704, Taiwan, Republic of China ReceiVed February 13, 2008
1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC50 of 0.9 and 0.6 µM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and combretastatin A-4. They also showed antiproliferative activity with IC50 of 0.3-5.4 nM in a set of human cancer cell lines. Introduction One of the currently useful chemotherapy drugs in oncology is represented by antimitotic agents, for example, taxanes and vinca alkaloids.1 However, the issues of high systemic toxicity, complex syntheses, drug resistance, and isolation procedures have encouraged scientists to develop new antimitotic agents. Recent literature reported that the antitubulin agents targeting the colchicine-binding domain rapidly depolymerize microtubules of vasculatures changing morphology in the endothelial cells of tumor’s vessels to block the blood supply to tumors and can act as vascular-disrupting agents,2 for example, 2, 3, and 5 (Figure 1). The encouraging antivascular and antitumor prolife of 2 has stimulated interest in design and synthesis of a variety of derivatives or analogues.3 One of the modified sites in combretastatin structure is the olefin functionality of Z-stilbene; for instance, it was replaced with a 1,3-diaryl five-member ring (oxazoline and oxadiazoline),4 1,2-diaryl five-member ring (triazole,5 pyrazole, tetrazole, thiazole,6 imidazole,7 furan,8 furazan9), carbonyl bridge,10 and 2- or 3-carbonylthiophene.11 Attempts to replace the double bond bridge in 1 with an amide bond resulted in dramatic loss of activity12 (6 vs 1). Despite this, the amide moiety was used for isosteric replacement with an olefin group.13 In this paper, we use 6 as a base to design a series of heterocyclic analogues of 1 to improve activity by a restricted approach connecting the amide moiety and the B-ring of 6 via a five- or six-member ring to introduce a series of 1-aroylindolines, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindoles (Figures 2 and 3). Here, we describe the discovery of
* To whom correspondence should be addressed. For H.-P.H.: (phone) 886-37-586-456,ext35708;(fax)886-37-586-456;(e-mail)
[email protected]. For J.-Y.C.: (address) 2F, No. 367, Sheng Li Road, Tainan 704, Taiwan, Republic of China; (phone) 886-6-700-0123, ext 65100; (fax) 886-6-2083427; (e-mail)
[email protected]. † Taipei Medical University. ‡ National Institute of Cancer Research, National Health Research Institutes. ¶ Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes. § National Cheng Kung University Hospital.
Figure 1
4-amino- and 4-hydroxy-1-aroylindoles as novel, highly potent antimitotic agents. Results and Discussion Chemistry. Diphenylamide 612 was prepared as shown in Scheme 1. To synthesize 7 and 9, 5-methoxyindole (28) and 2-methyl-5-methoxyindole (29) were treated with sodium cyanoborohydride in acetic acid to give indoline 30 and 31, respectively (Scheme 2). The electrophilic substitution of 30 and 31 with the 3,4,5-trimethoxybenzoyl chloride in pyridine gave the desired 1-aroylindoline 7 and 9 in 87% and 88% yield, respectively. The 1-aroyl-1,2,3,4-tetrahydroquinoline 8 was prepared in 89% yield by treatment of commercially available 1,2,3,4-tetrahydroquinoline (32) with 3,4,5-trimethoxybenzoyl chloride in pyridine (Scheme 3). The general method for the synthesis of 1-aroylindoles 1014-14, 17,14 20, and 24 is depicted in Scheme 4. The direct electrophilic substitution of 3,4,5trimethoxybenzoyl chloride at the N1-position of various commercially available indoles in the presence of KOtBua gave the desired 1-aroylindoles in 25-95% yield. Compounds 15 a Abbreviations: KOtBu, potassium tert-butoxide; TBDMSCl, tertbutyldimethylsilyl chloride; NaBH3CN, sodium cyanoborohydride; K2CO3, potassium carbonate; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; MDR, multidrug-resistant; TBAF, tetra-n-butylammonium floride.
10.1021/jm800150d CCC: $40.75 2008 American Chemical Society Published on Web 06/28/2008
4352 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14
Brief Articles
Figure 3
Scheme 4a Figure 2
Scheme 1a
a Reagents and conditions: (a) 3,4,5-trimethoxybenzoyl chloride, pyridine, room temp.
Scheme 2a
a Reagents and conditions: (a) 3,4,5-trimethoxybenzoic anhydride, KtOBu, THF.
Scheme 5a
a Reagents and conditions: (a) (i) LiAlH4, THF; (ii) imidazole, TBDMSCl, DMF, 0 °C; (b) (i) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF; (ii) TBAF, THF, 0 °C; (c) (CH3)2NH · HCl, Et3N, NaBH3CN, EtOH; (d) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF.
a Reagents and conditions: (a) AcOH, NaBH3CN; (b) 3,4,5-trimethoxybenzoyl chloride, pyridine.
Scheme 3a
a
Reagents and conditions: (a) 3,4,5-trimethoxybenzoyl chloride, pyridine.
and 16, with a C5-hydroxymethyl and C5-dimethylaminomethyl groups, respectively, were prepared by starting from the indole5-carboxyaldehyde (33) as shown in Scheme 5. Dimethylamine/ sodium cyanoborohydride mediated reductive amination of 33 followed by electrophilic substitution with 3,4,5-trimethoxybenzoic anhydride gave 16 in 37% yield (two steps). Compound 33 was converted into the desired the C5-hydroxymethyl 15 in 23% yield in four steps: LiAlH4-mediated reduction, protection
by TBDMSCl, indole N1-aroylation, and fluoride-mediated desilylation. Compound 19, with a C5-dimethylamino substituent, was synthesized starting from the 2-methyl-5-nitroindole (36), which on N1-aroylation with 3,4,5-trimethoxybenzoyl chloride in the presence of NaH followed by Fe/NH4Cl-mediated reduction afforded 18. The amine 18 was converted into the desired C5-dimethylamino 19 in 30% yield by reaction with iodomethane in the presence of K2CO3 and DMF (Scheme 6). The modification at the C2-position of 10 by the hydroxy and amino moieties, giving 21 and 22, were prepared as shown in the Schemes 7 and 8, respectively. Starting from the ethyl 5-methoxyindole-2-carboxylate (38), the synthesis of 21 was carried out in four steps through LiAlH4-mediated reduction, protection with the tert-butyldimethylsilyl group, N1-aroylation with 3,4,5-trimethoxybenzoic anhydride, and deprotection with tetrabutylammonium fluoride in 21% yield (four steps, Scheme 7). Compound 22 was synthesized starting from the 5-methoxyindole-2-carboxyaldehyde (41), which was subjected to the
Brief Articles
Scheme 6a
a Reagents and conditions: (a) NaH, 3,4,5-trimethoxybenzoyl chloride, toluene, DMF; (b) Fe, NH4Cl, isopropanol, H2O, reflux; (c) CH3I, K2CO3, DMF.
Scheme 7a
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14 4353
Scheme 10a
a Reagents and conditions: (a) (i) TBDMSCl, Et3N, CH2Cl2; (ii) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF, room temp; (iii) TBAF, THF, 0 °C.
Table 1. IC50 Values of Compounds 6-27, 4, and 1 cell type (IC50 ( SD,a nM) compd
a Reagents and conditions: (a) LiAlH4, THF, room temp; (b) imidazole, TBDMSCl, DMF, 0 °C; (c) (CH3)2NH · HCl, Et3N, NaBH3CN, CH2Cl2; (d) (i) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF, room temp; (ii) TBAF, THF, 0 °C to room temp; (e) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF.
Scheme 8a
a Reagents and conditions: (a) (i) imidazole, TBDMSCl, DMF, 0 °C; (ii) KOtBu, 3,4,5-trimethoxybenzoic anhydride, THF; (iii) TBAF, THF, 0 °C; (b) CH3I, K2CO3, DMF.
Scheme 9a
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 4 1
KB
H460
MKN45
KB-vin10
>5000 89 ( 2.9 596 ( 123 370 ( 33 208 ( 58 371 ( 111 575 ( 55 >5000 >5000 >5000 >5000 18 ( 6 345 ( 17 42 ( 21 230 ( 71 >5000 >5000 >5000 >5000 >5000 1.2 ( 0.4 0.3 ( 0.3 11.4 ( 1 2.2 ( 0.3
>5000 98 ( 1 652 ( 32 413 ( 6 232 ( 21 353 ( 75 559 ( 81 >5000 >5000 >5000 >5000 23 ( 7 334 ( 84 52 ( 7 198 ( 1.4 >5000 >5000 >5000 >5000 >5000 5.4 ( 1.2 0.5 ( 0.4 20 ( 2 2.8 ( 0.8
>5000 53 ( 1.4 395 ( 51 257 ( 30 198 ( 13 314 ( 35 521 ( 51 >5000 >5000 >5000 >5000 17 ( 3 156 ( 54 41 ( 13 101 ( 19 >5000 >5000 >5000 >5000 >5000 3.1 ( 2.3 0.6 ( 0.8 11 ( 1 5.6 ( 0.2
>5000 84 ( 11 586 ( 82 372 ( 18 197 ( 20 400 ( 80 587 ( 42 >5000 >5000 >5000 >5000 11 ( 4 312 ( 20 38 ( 14 185 ( 21 >5000 >5000 >5000 >5000 >5000 2.4 ( 1.3 0.3 ( 0.2 125 ( 10 1.8 ( 0.4
a SD: standard deviation. All experiments were independently performed at least three times.
a Reagents and conditions: (a) KOH, tetrabutylammonium bisulfate, PhSO2Cl, CH2Cl2; (b) HNO3; (c) (i) NaOH, EtOH, reflux; (ii) KOtBu, 3,4,5trimethoxybenzoic anhydride, THF; (d) Fe, NH4Cl, isopropanol, H2O, reflux.
reductive amination of C2-aldehyde in the presence of (CH3)2NH and NaBH3CN to give unexpected 42 that followed by indole N1-aroylation with 3,4,5-trimethoxybenzoic anhydride, affording 22 (Scheme 7). Compound 23, the C3-ethyl carboxylate analogue of 17, was prepared starting from commercially available 43 by treating with the TBDMSCl/imidazole, 3,4,5trimethoxybenzoic anhydride/KOtBu, and then tetrabutylammonium fluoride to give 44. The O-methyation of 44 in the presence of CH3I and K2CO3 afforded the desired 23 in 52% yield (Scheme 8). Compound 26, with an additional amino group at the 4-position of indole in 10, was prepared by starting from the 5-methoxyindole (28) in five steps, as shown in the Scheme 9. N1-Benzenesulfonyl protection of 28 followed by nitration15 gave the 5-methoxy-4-nitro-substituted indole 46. The N1benzenesulfonyl of 46 was deprotected with NaOH and then treated with the 3,4,5-trimethoxybenzoic anhydride in the presence of KOtBu and THF and then subjected to Fe-mediated reduction to give the desired 26 in 16% overall yield (five steps). Compound 27, with an additional hydroxyl group at the 4-position of 1-aroylindole 17, was synthesized from the key
material 47, which was prepared by the literature methodology.16 The 4-hydroxy-2-methyl-5-methoxyindole (47) was converted into the 4-hydroxy-1-aroylindole 27 in three steps via the protection with tert-butyldimethylsilyl group, N1-aroylation with 3,4,5-trimethoxybenzoic anhydride, and fluoride ion-mediated deprotection to afford the desired 27 in 19% yield (Scheme 10). Biological Evaluation. (A) In Vitro Cell Growth Inhibitory Activity. The synthesized 1-aroylindolines 7 and 9, 1-aroyl1,2,3,4-tetrahydroquinoline 8, and 1-aroylindoles 10-27 were evaluated for antiproliferative activities against three types of human cancer cell lines, oral epidermoid carcinoma KB cells, non-small-cell lung carcinoma H460 cells, and stomach carcinoma MKN45 cells, as well as one type of MDR-positive cell line, KB-vin10 cells, overexpressed P-gp 170/MDR (Table 1). We first evaluated the effect of adding a five- or six-member ring upon the B-ring of 6, i.e., to cyclize the amide bond and B-ring in 6, for cytotoxicity activity. Indoline 7, tetrahydroquinoline 8, and indole 10 were evaluated for antiproliferative activity. Structure-activity relationships indicated that the fivemember ring based heterocycles, 1-aroylindoline (7) and 1-aroylindole (10), and the six-member ring based heterocycles, 1-aroyltetrahydroquinoline (8), all show stronger activity than the parent (6), with mean IC50 values of 81, 208, 557 nM against four lines, respectively. On the basis of these results of fivemember-ring-containing heterocyclic analogues showing good cellular growth inhibitory activity, the substituted 1-aroylindoline
4354 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14
derivative (9) and 1-aroylindole derivatives (11-27) were further prepared and evaluated for activity. In the SAR study of 1, the p-methoxy substitution of the B-ring of Z-stilbene plays a pivotal role for activity.10a,12 So we prepared 11-16 with a methyl, methylenedioxy, methylcarboxylate, carboxyaldehyde, hydroxymethyl, and dimethylaminomethyl groups at the 5- or 5,6-postion of 1-aroylindoles. Compounds 11 and 12, with electron-donating groups C5-methyl and C5,6-methylenedioxy groups, respectively, slightly reduced the activity compared to 10. But changing the C5-methoxy group of 10 to electron-withdrawing CO2CH3 and CHO groups in 13 and 14, respectively, resulted in drastic loss of activity. Compounds 15 and 16, with a CH2OH and CH2N(CH3)2 group at C5-postion, respectively, displayed no activity, thus revealing that the steric effect of substituents at C5-position may influence cellular growth inhibitory activity. In order to investigate the effect of substitution at C2-position of 1-aroylindoles, 17, 20, 21, and 22 with an alkyl, ester, alcohol, and amine functionalities, respectively, on the 2-indole were tested for their antiproliferative activity. Compound 17, with a C2-methyl substitution on the 1-aroylindole 10, showed the most potent activity, changing to the C2-ethyl carboxylate substitution (20), which resulted in moderate activity with mean IC50 of 178 nM against four lines comparable to the that of 10, while changing to the alcohol or amino functionalities (21 and 22) decreased the activity drastically. On the basis of these results (C2-modification), the introduction of an alkyl or ester functional group at the C2-position of 1-aroylindoles seems to be preferable in activity. The introduction of a methyl group at the C2-position of 1-aroylindoles exerted a potency increase that intrigued us to explore whether 1-aroylindolines also exhibit this effect. Contrary to expectation, 9 with an additional methyl group in 1-aroylindoline 7 showed a decreased growth inhibition by a >3-fold magnitude in four cell lines (9 vs 7). As the C2-ethyl carboxylate substitution in 1-aroylindoles (20) exhibited moderate cytotoxicity, 23 and 24, with the CO2Et and CH2N(CH3)2 groups at the C3-position, respectively, were also prepared. But no activity was observed in 23 and 24. A literature report12 showing that the 4-methoxy group in the B-ring of 1 skeleton can be replaced with a 4-N,N-dimethylamino group inspired us to synthesize 19, with the C2-methyl and C5-dimethylamino groups on the indole ring. Indeed, 19 demonstrated strong antiproliferative activity in four cell lines, with mean IC50 values of 43 nM. In an effort to increase the corresponding 1-aroylindoles structure’s polarity, the 4-amino and 4-hydroxy-substituted 1-aroylindoles 26 and 27 were prepared to mimic the structure of 3 and 2 with a amino and hydroxy group at the C3′-position of B-ring of Z-stilbene, respectively. Compound 26, namely, 4-amino-5-methoxy-1-(3′,4′,5′-trimethoxybenzoyl)indole, displayed a mean IC50 of 3.0 nM against four cell lines comparable to the reference compound 1 (IC50 ) 3.1 nM). Compound 27, with a hydroxyl group at C-4 position of indole ring, namely, 4-hydroxyl-2-methyl-5-methoxy-1-(3′,4′,5′-trimethoxybenzoyl)indole, showed mean a IC50 of 0.42 nM in all four lines, thus exhibiting stronger cytotoxicity than 1. Interestingly, 26 and 27 with additional amino and hydroxyl groups showed approximately >10-fold improvement in IC50 values over analogues 10 and 17, respectively (26 vs 10; 27 vs 17). Hence, it may be concluded that the introduction of an amino or hydroxyl group at the C-4 position of 1-aroylindoles, in addition to a methoxy group at C-5 position, is important for maximal cytotoxicity.
Brief Articles Table 2. Inhibition of Tubulin Polymerization and Colchicine Binding by Compounds 7, 8, 10, 19, 26, 27, 4, and 1 compd 7 8 10 19 26 27 4 1
tubulina IC50 ( SD (µM) 2.6 ( 0.3 >5 2.5 ( 0.6 1.5 ( 0.5 0.9 ( 0.2 0.6 ( 0.1 3.0 ( 0.4 1.1 ( 0.3
colchicine bindingb ( SD (%) 1 µM inhibitor
5 µM inhibitor
27 ( 2
55 ( 3
45 ( 3 72 ( 1 71 ( 2 94 ( 1
72 ( 2 89 ( 1 93 ( 1 97 ( 0.5
85 ( 0.2
93 ( 2
a
Inhibition of tubulin polymerization.17 Tubulin was at 1 µM. b Inhibition of [3H]colchicine binding. [3H]Colchicine was at 5 µM.
(B) Inhibition of Tubulin Polymerization and Colchicine Binding Activity. To examine whether 1-aroylindoline, 1-aroyltetrahydroquinoline, and 1-aroylindoles were tubulin inhibitors through the colchicine-binding site, the selected compounds 7, 8, 10, 19, 26, 27 and reference compounds (1 and 4) were evaluated for antitubulin activity and the ability to compete for the colchicine-binding site (Table 2). Results indicated that the compounds’ antiproliferative activity positively correlated with the inhibition of tubulin polymerization. Compounds 19, 26, and 27 were efficacious in inhibiting microtubulin assembly, with IC50 values of 1.5, 0.9, 0.6 µM, respectively. In the [3H]colchicine binding assay, data indicated the 4-amino-1aroylindoles (26) and 4-hydroxy-1-aroylindoles (27) were strongly bound to the colchicine-binding domain on microtubulin. Compound 27 showed substantial activity. It inhibited colchicine binding by 94% (27 was 1 µM with colchicine at 5 µM) and 97% (27 was 5 µM with colchicine at 5 µM). Conclusion Synthesis and structure-activity relationship of synthetic anticancer agents 1-aroylindoline, 1-aroyltetrahydroquinoline, and 1-aroylindoles skeleton were described. The synthesized 1-aroylindoline (7) and 1-aroylindoles (19, 26, and 27) are potent cytotoxic agents and antitubulin agents acting through the colchicine-binding site on tubulin. Compounds 19, 26, and 27 displayed antiproliferative activity with IC50 values of 38-52, 1.2-5.4, and 0.3-0.6 nM, respectively, in a variety of human cancer cell lines from different organs. They also showed substantial antitubulin activity with IC50 values of 1.5, 0.9, and 0.6 µM, respectively. SAR data revealed that the introduction of amino or hydroxyl group at the C4-position of 1-aroylindole series significantly increased activity than the parent (26 vs 10; 27 vs 17). Thus, the amino or hydroxyl substituents located at position 4 of 1-aroylindole moieties apparently plays an important role in the activity of this series of compounds. Utilizing a restricted approach of drug design, we effectively converted inactive diphenylamide 6 into active compounds, for example, 1-aroylindoline (7 and 9), 1-aroyltetrahydroquinoline (8), and 1-aroylindoles (10-12, 17-20, 26, and 27), with substantial activity. This information maybe can be applied to other corresponding tubulin inhibitors or combretastatin analogues modification. Experimental Section 4-Hydroxy-5-methoxy-2-methyl-1-(3′,4′,5′-trimethoxybenzoyl)indole (27). To a solution of 47 (1.46 g, 8.24 mmol) and triethylamine (2.29 mL, 16.48 mmol) in CH2Cl2 (20 mL) was added tert-butyldimethylsilyl chloride (1.86 g, 12.36 mmol) at room temperature. After the mixture was stirred for 18 h, the reaction was quenched with water and the layer was extracted with CH2Cl2 (30 mL × 3). The combined organic layer was dried over anhydrous
Brief Articles
MgSO4 and concentrated under reduced pressure to give a yellow oil residue, which was treated with potassium tert-butoxide (1.39 g, 12.36 mmol) in the presence of THF (50 mL) and stirred for 15 min at room temperature. The 3,4,5-trimethoxybenzoyl chloride (2.14 g, 9.27 mmol) was added to the reaction mixture. After 1 h, the solvent was evaporated and the residue was neutralized with NaHCO3(sat.) and then extracted with EtOAc (20 mL × 2) and CH2Cl2 (20 mL × 2). The combined organic layers were dried over MgSO4 and evaporated to give a residue, which was dissolved in THF (20 mL) and then was subjected to 1.0 M tetra-n-butylammonium floride/THF (12.4 mL) with stirring at 0 °C for 1 h. The reaction mixture was evaporated and purified by silica gel chromatography (EtOAc/n-hexane ) 1: 3; recrystallized by EtOAc/nhexane) to afford 27 as a yellow crystalline solid: yield 19%, mp 153-155 °C. 1H NMR (500 MHz, CDCl3): δ 2.39 (s, 3H), 3.82 (s, 6H), 3.88 (s, 3H), 3.95 (s, 3H), 5.76 (br, 1H), 6.53 (s, 1H), 6.63 (d, J ) 8.9 Hz, 1H), 6.69 (d, J ) 8.9 Hz, 1H), 6.95 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 15.8, 56.3, 57.1, 61.1, 105.1, 105.7, 107.0, 107.8, 118.5, 130.3, 133.5, 137.0, 137.6, 141.1, 141.8, 153.1, 169.3. MS (EI) m/z: 371 (M+, 44%), 195 (100%). HRMS (EI) for C20H21NO6 (M+): calcd, 371.1371; found, 371.1370. Anal. (C20H21NO6 · 0.5H2O) C, H, N.
Acknowledgment. This research was supported by the National Science Council of the Republic of China (Grants NSC 96-2320-B-038-003, NSC 96-2752-B-400-001-PAE, and NSC95-2113-M-400-001-MY3) and by National Health Research Institutes, Taiwan (Grant CA-097-PP-02). Supporting Information Available: Spectral data of 6-26, 37, 42, 44, 46 and details for synthesis and biological evaluations. This material is available free of charge via the Internet at http:// pubs.acs.org.
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